A large number of drugs are inducers of sleep. There are also many drugs exhibiting awakening action. However, these drugs pose problems of drug resistance and drug dependence in prolonged use. Additionally, these drugs do not improve “the quality of sleep” for the purpose of treating aging-related sleep disorders. Furthermore, no drugs are available that ameliorate learning and memory disorders that develop with aging. With the aging of the general population, the ratio of people suffering a quantitative or qualitative reduction in their sleep is increasing. Various cerebral disorders that develop due to aging-related brain hypofunction have major difficulties not only on patients, but also on society as a whole.
To date, central nervous stimulants and sleep-inducing drugs have been used for sleep disorders. Most of them target the neurotransmitter pathways, and many are short-time acting, though the persistency of action varies among different agents. Both central nervous stimulants and sleep-inducing drugs have a risk to cause adverse reactions such as dependence, habituation, and transient amnesia, many of which are designated narcotics by law.
Sleep, one of the most fundamental physiological functions of organisms, is essential for their survival. Although its physiological significance is still disputable, sleep is thought to be involved in higher brain functions such as recovery from psychosomatic fatigue and memory fixation and reconsolidation.
Based on electromyographic and electroencephalographic analyses, sleep can be divided into two stages: non-REM sleep, characterized by decreased brain function, and REM sleep, where brain function is active but skeletal muscles are relaxed. What is called deep sleep, slow wave sleep, belongs to non-REM sleep. Although the ratio of REM and non-REM sleep stages and the length of sleep differ among different biological species, REM sleep and slow wave sleep are also observed in mice and other non-human animals.
The REM sleep stage is thought to be particularly important to ensure that higher brain functions such as memory fixation and reconsolidation occur normally.
Sleep disorders are roughly divided into two categories: hypersomnia and asomnia. Typical conditions are narcolepsy in the former and insomnia in the latter. Caused by a broad range of factors, sleep disorders are induced in case of forced time shifts such as jet lags and shift work, or with stress due to overwork and the like. Meanwhile, many cases of sleep disorders accompany some other diseases; cardiac function abnormalities, obesity and the like are likely to lead to inadequate sleep. Sleep disorders also occur as adverse reactions to many drugs. For example, antipyretics, antiallergic remedies, gastrointestinal drugs such as H2 blockers induce drowsiness. Furthermore, brain function disorders, e.g., schizophrenia, bipolar disorders, Alzheimer's disease, Parkinson's disease are sometimes accompanied by sleep disorders.
In general, the quality and quantity of sleep decrease with age. Experiencing difficulty in falling asleep, early wakeups, diminished wake-sleep rhythms between day and night, decreased REM sleep, decreased slow wave sleep and the like, many people in their senescence are somewhat dissatisfied with their sleep. Furthermore, many prescribed drugs (for symptoms other than sleep-related ones) disturb sleep as adverse reactions, and most elderly people are on medication with one or more drugs prescribed; it is somewhat difficult to elucidate the causes of their complaints regarding sleep and take countermeasures. Described below are some currently available therapeutic drugs for sleep disorders.
Central Nervous Stimulants
Amphetamine or chemically synthesized stimulants with similar structure have long been used to suppress narcolepsy and daytime drowsiness in shift works. As an indirect adrenergic agonist, amphetamine potently stimulates the central nervous system by promoting the release of noradrenaline and dopamine, inhibiting their reuptake, and inhibiting monoamine oxidase (MAO). Its use is prohibited in Japan for the reason of adverse reactions in prolonged use or overuse. Modafinil is used in the US since it is unlikely to produce habituation and adverse reactions, although its action point remains unknown. Contained in foods, caffeine exhibits stimulatory action; it is thought to be safe when taken in appropriate amounts, but it causes mild dependency.
Sleep-Inducing Drugs
Commonly prescribed sleep-inducing drugs include brotizolam (Lendormin), triazolam (Halcion), flunitrazepam (Rohypnol), Silece, Amoban and the like; these act mainly on receptors of the inhibitory neurotransmitter GABA; adverse reactions such as motor disorders, memory disorders, drug dependence, and carryover effects are problematic in long-term use.
Drugs that are more effective on GABA-A receptors, e.g., zolpidem (Ambien), zaleplon (Sonata), zopiclone (Imovane), and eszopiclone (Lunesta), all decrease REM sleep to promote sleep onset, and are mostly effective in suppressing the transition from slow wave sleep to wakefulness. These sleep-inducing drugs are also effective as sedatives, and have been reported to produce unusual behavior as adverse reactions while the user is in an anti-wake state.
As such, the sleep-inducing drugs and central nervous stimulants act directly on the neurotransmitter pathway, so that their effects usually occur instantaneously; they must be taken just before expecting an effect (within several hours). Because the targeted neurotransmitter pathway is not associated exclusively with sleep, they cause serious disorders when taken in large amounts. Additionally, prolonged use leads to a reduction in the responsiveness of the neurotransmission pathway, which can cause drug dependence. Furthermore, the rebound phenomenon following drug discontinuation is considerable to the extent of likely habituation, thus increasing the risk of drug dependence.
Although melatonin is prescribed for mild cases of sleep disorders, especially for those due to a shift of circadian rhythm, it is not positively prescribed by specializing physicians because of a lack of difference in clinical efficacy compared with phototherapy.
N-acetyl-D-mannosamine, an isomer of N-acetyl-D-glucosamine, is known as, for example, a starting material for the enzymatic synthesis of sialic acid (N-acetyl-neuraminic acid), which serves as a medicament and a starting material for other medicaments. Also, N-acetyl-D-mannosamine permits enzymatic synthesis of sialic acid derivatives from derivatives thereof, hence an industrially important substance. In a known method of producing N-acetyl-D-mannosamine, the molar conversion yield of N-acetyl-mannosamine from N-acetyl-glucosamine in isomerizing the latter under alkaline conditions is increased by the addition of boric acid or borate (JP-A-HEI-10-182685). Another known method is such that sialic acid, as the substrate, is reacted with N-acetyl-neuraminate lyase to produce N-acetyl-D-mannosamine (JP-A-2001-78794). A method has been proposed wherein the acylated form of N-mannosamine is contacted with cells to regulate lectin binding to cell surfaces or to regulate the proliferation of nerve cells (U.S. Pat. No. 6,274,568).
N-acetyl-D-mannosamine is utilized as a starting material for the synthesis of sialic acid or an intermediate for medicaments. As the situation stands, however, it is not used as a final product in medicaments or foods. Furthermore, there is no knowledge that N-acetyl-D-mannosamine is effective in ameliorating brain hypofunction and in ameliorating sleep disorders.